Project Abstract This SBIR Phase II proposal is based on our strong pre-clinical data and SBIR phase I results, and will support a Phase II clinical trial to examine the efficacy and toxicity of the combination of PDMX1001 (niclosamide) with abiraterone for the treatment of enzalutamide-resistant Castration-Resistant Prostate Cancer (CRPC), and conduct molecular correlative studies. Our goal is to develop a novel treatment strategy for advanced prostate cancer by targeting both full-length androgen receptor (AR-FL) and androgen receptor variant 7 (AR-V7) signaling. Abiraterone and enzalutamide are frequently used in treating CRPC. However, the response duration is usually short, and resistance to abiraterone and enzalutamide is the most common cause of treatment failure. Even though both drugs are often effective initially, after CRPC develops resistance to one drug, the response rate to the other drug is around 20% or less. Considerable evidence from both clinical and experimental studies demonstrated that AR-V7 plays vital roles in induction of resistance to both drugs. AR-V7 is not targeted by either abiraterone or enzalutamide. Therefore, there is urgent need to develop novel agents that target AR-V7 to overcome resistance. We discovered PDMX1001 as a potent inhibitor of AR-V7, and obtained extensive preclinical data showing that PDMX1001 synergizes abiraterone in treating CRPC. Based on our previous pre-clinical findings, we conducted a Phase Ib clinical trial (NCT02807805) funded by an SBIR Phase I grant (1R43CA206668-01) and confirmed that the PDMX1001 and abiraterone combination treatment is safe and effective in CRPC patients. The promising SBIR Phase I results lay foundation for this SBIR phase II study to conduct a single-arm Phase II clinical trial to determine the efficacy and toxicity of the combination therapy of PDMX1001 and abiraterone in enzalutamide resistant CRPC patients. We will also conduct molecular correlative studies in these patients. This project, if successful, is high yielding and will greatly benefit hundreds of thousands of prostate cancer patients every year.